Oral administration of pharmaceuticals is one of the most widely used methods of providing therapy to treat a variety of illnesses. Many medications are orally administered to a person in a dosage form such as a tablet, capsule, or liquid. Such medications can be administered buccally, sublingually, or swallowed for release into the digestive tract.
In order for a drug to achieve its desired result, it typically must be delivered to a biological site of interest. The vast majority of drugs in use today are solid ingestibles. In order for these drugs to be absorbed into the bloodstream and transported to a biological site of interest, they usually must first be dissolved and then permeate the intestinal walls. The drugs must also avoid first pass metabolism, which occurs when the drugs are removed from the bloodstream as they pass through the liver.
Modern high throughput screening and combinatorial chemistry drug discovery methods may be used to produce high potency drugs with high specificities. As affinities for targeted cell sites increase, however, the lipophilicity of the compounds tends to increase. Conversely, the aqueous solubility of the compounds tends to decrease. A decrease in the aqueous solubility of a compound typically results in a corresponding decrease in the dissolution rate of the compound. A drug with a low dissolution rate may pass through the digestive system without being absorbed in therapeutic quantities. Therefore, methods of delivering bioactive agents with high dissolution rates are desired. Drug candidates are frequently chemically modified to enhance their specificity, permeability, solubility, and dissolution rate, and trade-offs between these desired factors are made as the drug candidates are refined.
The preparation of small particles may increase the solubility and potentially the bioavailability of a selected drug candidate. Solubility may be modified by physically grinding a drug to yield micron size and smaller particles. However, this mechanical particle size reduction can cause chemical and/or physical degradation of the drug by shear and heat stress. Furthermore, particles less than 5 microns tend to agglomerate, which counters the benefits of micronization. Although agglomeration can be limited by creating liquid suspensions or emulsions, such liquids can have poor storage life because they can suffer from accelerated thermal degradation relative to solid state formulations.
Spray-drying and freeze-drying also may be used to generate small particles in an attempt to increase drug dissolution rates, and therefore bioavailability. However, agglomeration remains a problem. Another approach relies on the dissolution of the drug in organic solvents and subsequent precipitation by the addition of water or some other miscible solvent in which the drug is less soluble. However, it may be difficult or impossible to produce small particles with this method. Yet another alternative is to increase the dissolution rate of the drug by complexing the active drug entity with inclusion agents like cyclodextrins. For this to work the drug molecule should be amenable to inclusion into the cyclodextrin ring. Even then, the drug-cyclodextrin complex should be extensively tested for safety, which can be time consuming and expensive. Another approach utilizes the precipitation of a drug-polymer mixture, resulting in the production of small (i.e. micrometer-sized) particles are produced. However, in this case, the polymer typically remains as an “additive” in the resulting particles.